Functional Recovery of Diabetic Mouse Hearts by Glutaredoxin-1 Gene Therapy: Role of Akt-FoxO Signaling Network

Recent studies suggest that glutaredoxin-1 (Glrx-1) may serve as therapeutic target for diabetic hearts. Since the level of reactive oxygen species (ROS) is increased in the pathologic hearts including ischemia/reperfusion (I/R) and diabetes, we assumed that upregulation of Glrx-1 could reduce the cardiac risk factors associated with I/R and/or diabetes. Diabetes was induced in mice by i.p. injection of streptozotocin (150 mg/kg). Eight days after when the blood glucose was elevated to 400 mg/dL, the animals were randomly assigned to one of the following three groups, which received either empty vector, or LacZ or Glrx-1 adenoviral construct. Four days later, isolated working hearts were subjected to 30 min ischemia followed by 2 h reperfusion. Glrx-1 gene therapy significantly enhanced the Glrx-1 level, which prevented I/R-mediated reduction of ventricular recovery, increased myocardial infarct size and cardiomyocyte apoptosis in diabetic myocardium. In concert, Glrx-1 prevented diabetes and ischemia-reperfusion induced reduction of cardioprotective proteins including Akt, FoxO-1, and hemeoxygenase-1 and abolished the death signal triggered by Jnk, p38 mitogen-activated protein kinase, and c-Src. Glrx-1 gene therapy appears to prevent cardiac complications in diabetic heart due to the I/R by switching the death signal into survival signal by activating Akt-FoxO-signaling network.